Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase

Hu, Anbin; Li, Jing; Tang, Wei; Liu, Ge; Zhang, Haiwei; Liu, Chunlan; Chen, Xulin

doi:10.3389/fmicb.2020.00178

Cited by 4 publications

(3 citation statements)

References 52 publications

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“…However, recent in vitro studies using HaCaT cells reveal profound metabolic changes by dithranol on a cellular level 22 , while there are also complex changes in inflammatory milieu and cytoskeleton on a tissue level 23 . Interestingly, dithranol also has direct antiviral properties by inhibiting the viral RNA polymerase of influenza virus 24 , suggesting dithranol has multiple effects on various cell types and in distinct contexts.…”

Section: Introductionmentioning

confidence: 99%

Dithranol as novel co-adjuvant for non-invasive dermal vaccination

et al. 2022

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Transcutaneous immunization (TCI) utilizing the TLR7 agonist imiquimod (IMQ-TCI) induces T cell-driven protective immunity upon application onto intact skin. In our present work, we combine the anti-psoriatic agent dithranol with IMQ-TCI to boost vaccination efficacy (Dithranol/IMQ-based transcutaneous vaccination (DIVA)). Using ovalbumin-derived peptides as model antigens in mice, DIVA induced superior cytolytic CD8+ T cells and CD4+ T cells with a TH1 cytokine profile in the priming as well as in the memory phase. Regarding the underlying mechanisms, dithranol induced an oxidant-dependent, monocyte-attracting inflammatory milieu in the skin boosting TLR7-dependent activation of dendritic cells and macrophages leading to superior T cell priming and protective immunity in vaccinia virus infection. In conclusion, we introduce the non-invasive vaccination method DIVA to induce strong primary and memory T cell responses upon a single local treatment. This work provides relevant insights in cutaneous vaccination approaches, paving the way for clinical development in humans.

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Section: Introductionmentioning

confidence: 99%

Dithranol as novel co-adjuvant for non-invasive dermal vaccination

et al. 2022

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“…ZINC000101564200 is structurally similar to anthralin (0.754) and emodin (0.711). Anthralin suppresses influenza A virus (IAV) proliferation [ 134 ] and has been shown to be an HIV-latency-reversing agent [ 135 ]. Therefore, ZINC000101564200 may be useful for EBOV latency reversal to completely eradicate EBOV from patients’ bodies.…”

Section: Resultsmentioning

confidence: 99%

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Broni

Ashley

Adams

et al. 2023

IJMS

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The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina’s capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of −8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (−46.97 to −118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

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“…DDB1-and CUL4-associated factor 7 (DCAF7) (log2Fc -1.7), Cullin-4A (CUL4A) (log2 Fc -2.3) and DNA damage-binding protein 1 (DDB1) (log2Fc -2.4) were downregulated in T1 (supplementary file 2). Another recent study implicated O-GlcNAcylation of SAMHD1 in promoting anti-HBV immunity as opposed to its anti-viral activity towards HIV (Hu et al, 2020), indicating another complex and crucial role of metabolic reprogramming underlying viral pathogenesis. The ubiquitin deconjugases encoded in the N-terminal domain of Epstein-Barr virus (EBV), Kaposi Sarcoma herpesvirus (KSHV) and human cytomegalovirus (HCMV) proteins were reported to target an early step of the IFN signaling cascade characterized by trimolecular complex formation with the ubiquitin ligase TRIM25 and the 14-3-3 molecular scaffold (Gupta et al, 2020).…”

Section: Extending the Interferon-ribosomal-rna Pathway Axis To Coagumentioning

confidence: 99%

Proteomic Profiling of Protease-Primed Virus-Permissive Caco-2 Cells Display Abortive-Interferon Pathway and Deregulated Thromboinflammatory SERPINS

Sharma¹,

Panda²

2020

Preprint

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Emerging paradigms in interferon (IFN) biology suggest a dynamic INF induced interactome that extends through broader Interferon Stimulated Gene (ISG)- induction, which implicates interferon- ISG coordinated cross-talk with mRNA processing, post-translational modification and metabolic processes that underlie pathological (viral, autoimmune and tumor biology) and physiological (stem cell regenerative pathways) processes. INF immune responses can also be triggered by endogenous host-derived molecules that are generated in response to cellular stress or hemostasis imbalance to establish tissue repair and regeneration in first place, however, overactivation or lack of countermeasures can result in host tissue damage. The proteases are integral to viral and tumor pathology, and importantly serine proteases TMPRSS2 and trypsin have been identified as important molecular determinants underlying COVID-19 pathology, and emergence of coronaviruses cultured in vitro, respectively. We propose that pathogen associated proteases can act as novel stress-inducers to facilitate viral- competent immunomodulation. We term it as Protease Induced Transcriptomic/ epi-Transcriptomic Reshaping (PITTR) of host cells to counter cellular stress. We present a novel experimental model and our preliminary findings of trypsin- primed Caco-2 cells (CPT) that result in translational halt comparable to cells grown under serum-starvation conditions (CSS). CPT at escalating trypsin concentration (CPT- EC) induce upregulation of selective proteins that majorly map to ribosomal, RNA transport, and spliceosome ribonucleoproteins (RNPs). The inclusion of proinflammatory IL1-b to CPT (CPT- IL) resulted in global overexpression of proteins comparable to Caco-2 cells cultured in growth-factor rich serum conditions (CFBS), indicating a likely de-repression of trypsin- induced translational halt. Caco-2 cells display abortive interferon proteome under differential trypsin conditions (CPT, CPT-EC and CPT-IL), which is marked by complete lack of INF generation despite induction of intermediate ISGs, suggestive of protease (trypsin)- dependent regulation of INF response. Viruses regulate the proteome of stress granules (SGs) that are induced to cope transient translational halt as a central adaptive response to pathogen induced cellular stress. The integral components of SGs include non-translating mRNA, ribonucleoproteins (RNPs) and RNA binding proteins (RBPs), which together form biological condensates through a biophysical process involving weak electrostatic interactions through intrinsically disordered regions in RBPs resulting in liquid- liquid phase separation. We compared the CPT- EC proteome to the Mammalian Stress Granules Proteome (MSGP) database to explore potential RBPs that could possibly regulate INF response (and could act as potential anti-viral targets). Notably, differentially upregulated RNPs and potential RBPs from ISG family including ADAR and PRKRA, and RNA helicases implicated in viral pathogenesis were found to be upregulated in the CPT- EC proteome further strengthening the role of proteases (trypsin) in regulating INF pathways independent of the pathogen. We propose that the supplementation of viable SARS-CoV-2 viral loads to trypsin- primed host cells could recapitulate an infectious disease model, which may closely phenocopy pathogen- driven inflammation and signaling events. Based on the global downregulation of seven SERPINS (serine protease inhibitors) linked to thromboinflammation in our LCMS profiling data, we support the candidature of serine protease inhibitors for protease mediated viral pathologies. COVID-19 is increasingly linked to coagulopathy and resemblance to Neutrophil Extracellular Trap (NET) related thromboinflammatory features; SERPIN A1AT (alpha 1 antitrypsin) being a potent neutrophil- elastase inhibitor and a negative regulator of coagulation complement pathway may be a promising candidate for establishing hemostasis rebalancing in COVID-19 pathology.

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Anthralin Suppresses the Proliferation of Influenza Virus by Inhibiting the Cap-Binding and Endonuclease Activity of Viral RNA Polymerase

Cited by 4 publications

References 52 publications

Dithranol as novel co-adjuvant for non-invasive dermal vaccination

Dithranol as novel co-adjuvant for non-invasive dermal vaccination

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Proteomic Profiling of Protease-Primed Virus-Permissive Caco-2 Cells Display Abortive-Interferon Pathway and Deregulated Thromboinflammatory SERPINS

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